The negative health implications of this trend toward adiposity are well established. They include increased risk of hypertension and coronary vascular disease, stroke, insulin resistance and type 2 diabetes mellitus. My colleagues and I have previously used the obese allele of the leptin gene to unmask the latent effects of other diabetes-susceptibility alleles present within the genomes of two mouse strains, C57BL/6J and BTBR. I mapped three quantitative trait loci to regions of mouse chromosomes 2, 16 and 19, and characterized a specific non-linear interaction between two loci that enhanced the diabetes-promoting effects of one locus in certain genetic backgrounds.
In that study, I was also surprised to find that the strong obesity-promoting effects of the ob allele could be modified extensively by strain background. Within the same population, I detected and mapped two different loci that segregate strongly with body weight gain.
Although an initial detection of linkage is an important step in the identification of the relevant disease genes, positional cloning requires localization of the genes with far greater precision than that afforded by studies of F2 mice, such as my own. Therefore, I have endeavored to generate a large panel of Interval Specific Congenic mouse lines to dissect each of the five gene loci with sub-centimorgan resolution. Two loci have successfully been mapped to small regions of chromosomes 2 and 19, respectively.
This manuscript discusses my efforts to support positional cloning of the genes, and to characterize the pathophysiological role of each of the loci in their respective disease syndromes. It also discusses my efforts to understand how loss of function of one gene, Stearoyl CoA Desaturase 1 (SCD1), promotes leanness in SCD1 knockout mice.
